Auranofin induces lethal oxidative and endoplasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia.
Auranofin induces lethal oxidative and endoplasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia.
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Auranofin诱导致命的氧化和内质网应激，并针对慢性淋巴细胞性白血病发挥有效的临床前活性。
DOI：
10.1158/0008-5472.can-13-2033
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发表时间：
2014-05-01
期刊：
影响因子：
11.2
通讯作者：
Bhalla KN
中科院分区：
文献类型：
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作者：
Fiskus W;Saba N;Shen M;Ghias M;Liu J;Gupta SD;Chauhan L;Rao R;Gunewardena S;Schorno K;Austin CP;Maddocks K;Byrd J;Melnick A;Huang P;Wiestner A;Bhalla KN
慢性淋巴细胞白血病（CLL）在最初的化学免疫治疗后表现出高缓解率，但随着治疗的复发，难治性疾病是最常见的结果，特别是在染色体11 q或17 p缺失的CLL中。在解决复发性疾病的治疗需求方面，我们报告了一种现有的美国食品和药物管理局批准的小分子药物的鉴定，以重新用于CLL治疗。金诺芬（Ridaura）被批准用于治疗类风湿性关节炎，但它在CLL细胞中表现出临床前疗效。通过抑制硫氧还蛋白还原酶活性和增加细胞内活性氧水平，金诺芬在培养的和原代CLL细胞中诱导致死性内质网应激反应。此外，金诺芬与血红素加氧酶-1和谷氨酸-半胱氨酸连接酶抑制剂对CLL细胞显示协同致死作用。金诺芬克服了保护性基质细胞介导的凋亡抵抗，并且还杀死了染色体11 q或17 p缺失的原代CLL细胞。在CLL的体内模型TCL-1转基因小鼠中，金诺芬治疗显著降低了肿瘤细胞负荷并改善了小鼠存活率。我们的研究结果为重新定位已批准的药物金诺芬用于CLL治疗的临床评价提供了依据。
Chronic lymphocytic leukemia (CLL) exhibits high remission rates after initial chemoimmunotherapy, but with relapses with treatment, refractory disease is the most common outcome, especially in CLL with the deletion of chromosome 11q or 17p. In addressing the need of treatments for relapsed disease, we report the identification of an existing U.S. Food and Drug Administration-approved small-molecule drug to repurpose for CLL treatment. Auranofin (Ridaura) is approved for use in treating rheumatoid arthritis, but it exhibited preclinical efficacy in CLL cells. By inhibiting thioredoxin reductase activity and increasing intracellular reactive oxygen species levels, auranofin induced a lethal endoplasmic reticulum stress response in cultured and primary CLL cells. In addition, auranofin displayed synergistic lethality with heme oxygenase-1 and glutamate-cysteine ligase inhibitors against CLL cells. Auranofin overcame apoptosis resistance mediated by protective stromal cells, and it also killed primary CLL cells with deletion of chromosome 11q or 17p. In TCL-1 transgenic mice, an in vivo model of CLL, auranofin treatment markedly reduced tumor cell burden and improved mouse survival. Our results provide a rationale to reposition the approved drug auranofin for clinical evaluation in the therapy of CLL.